WO2004075882A1 - Methods of preventing, treating and diagnosing disorders of protein aggregation - Google Patents
Methods of preventing, treating and diagnosing disorders of protein aggregation Download PDFInfo
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- WO2004075882A1 WO2004075882A1 PCT/CA2004/000272 CA2004000272W WO2004075882A1 WO 2004075882 A1 WO2004075882 A1 WO 2004075882A1 CA 2004000272 W CA2004000272 W CA 2004000272W WO 2004075882 A1 WO2004075882 A1 WO 2004075882A1
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
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- G—PHYSICS
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
Definitions
- the invention relates to methods for treating Alzheimer's Disease and other amyloidoses; more particularly, it relates to methods for inhibiting and reducing amyloid fibril formation in therapeutic intervention in Alzheimer's disease and other amyloidoses.
- Alzheimer's disease is characterized neuropathologically by amyloid deposits, neurofibrillary tangles, and selective neuronal loss.
- the major component of the amyloid deposits is amyloid- ⁇ (A ⁇ ), a 39-43 residue peptide. Soluble forms of A ⁇ generated from cleavage of amyloid precursor protein are normal products of metabolism.
- residues 1-42 (A ⁇ 42) in Alzheimer's disease was highlighted in the discovery that mutations in codon717 of the amyloid precursor protein gene, presenilin 1 and presenilin 2 genes result in an increased production of A ⁇ 42 over A ⁇ 1 -40.
- a ⁇ -fibrils may be an early and intervenable step during the progression of AD. Formation of amyloid plaques, as well as neurotoxicity and inflammation may be direct or indirect consequences of the interaction of A with molecules containing sugar moieties.
- a ⁇ interaction with glycosaminoglycans results in aggregation of A ⁇ possibly adding to their insolubility and plaque persistence.
- Glycosaminoglycans have also been implicated in neuronal toxicity and microglial activation.
- interaction with glycolipids such as gangliosides results in the stabilization and prevention of Ab fibril formation, as well as, the site of A ⁇ production.
- the family of phosphatidylinositols results in acceleration of fibril formation.
- the headgroup of phosphatidylinositol is myo- inositol, a naturally occurring simple sugar involved in lipid biosynthesis, signal transduction, and osmolarity control.
- amyloid deposition i.e. organs or tissues lying outside the central nervous system
- amyloid accumulation leading to organ dysfunction or failure.
- systemic organs i.e. organs or tissues lying outside the central nervous system
- amyloid accumulation leading to organ dysfunction or failure.
- Alzheimer's disease and "systemic" amyloid diseases there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
- U.S. Patent No. 4,847,082 discloses the use of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid for the treatment of Alzheimer's disease. It also discloses that isomers of phytic acid or phytate salt comprise the hexakisphosphate myo-inositol, hexakisphosphate scyl -mosito , hexakisphosphate D-cAz>oinositol, hexakisphosphate L-c zz ' ro-inositol, hexakisphosphate /zeo-inositol and hexakisphosphate muco-mosito conformations.
- Phytic acid is inositol- hexakisphosphate (IP6).
- IP6 inositol- hexakisphosphate
- U.S. Patent No. 5,112,814 discloses the use of phytic acid and isomers thereof for the treatment of Parkinson's disease. As is the case with U.S. Patent No.
- AD Alzheimer's disease
- Alzheimer's disease Much work in Alzheimer's disease has been accomplished, but little is conventionally known about compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses.
- New compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses are therefore urgent needed.
- the present invention provides a method of treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence comprising administering to said subject a pharmaceutically effective amount of compound selected having the following structure:
- each of Rmetabol R,,, R 2 , R 2 ,, R 3 , R 3 ,, R 4 , R 4 ., R 5 , R 5 ,, R g , and R 6 . is independently selected from the group of:
- NHR7 wherein said R7 is selected from the group of hydrogen; C2- Cjo acyl and C ⁇ -CIQ alkyl;
- RJQ is selected from the group of no group, hydrogen, C2-C10 acyl, C 1-C10 alkyl and SO3H;
- the present invention also provides a method of preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions in a subject comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
- each of R privilege R r , R 2 , R 2 ., R 3 , R 3 ., R , R 4 -, R 5 , R 5 ., R 6 , and R 6 . is independently selected from the group of:
- NHR7 wherein said R7 is selected from the group of hydrogen; C2- Cjo acyl and Ci-Cjo alkyl;
- Rj Q wherein said Rj 0 is selected from the group of no group, hydrogen, C2-C10 acyl, C I-CJQ alkyl and SO3H;
- each of R privilege R r , R 2 , R 2 ., R 3 , R 3 ., R 4 , R >, R 5 , R 5 ,, R 6 , and R 6 . is independently selected from the group of:
- NHR7 wherein said R7 is selected from the group ofhydrogen; C2- C ⁇ 0 acyl and C ⁇ -C ⁇ Q alkyl;
- Ri 0 is selected from the group of no group, hydrogen, C2-C10 acyl, C i-C ⁇ o alkyl and SO3H; (e) C5-C7 glycosyl;
- SRj 1 wherein R ⁇ is selected from the group ofhydrogen, Cj-Cio alkyl and O3H; (h) C 1 -C ⁇ 0 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR ⁇ o > NHR7, NR R9 and SRjj; and (i) C3 ⁇ Cg cycloalkyl optionally substituted with a substituent selected from the group ofhydrogen, ORJQ, NHR7, NRgRp and SRj ⁇ providing that the compound is riot myo-inositol.
- the present invention also provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and (b) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- each of R privilege R r , R 2 , R 2 ., R 3 , R 3 ,, R 4 , R 4 ,, R 5 , R 5 ,, R 6 , and R 6 is independently selected from the group of:
- NHR7 wherein said R7 is selected from the group ofhydrogen; C2- CJO ac yl and Ci-CjQ alky
- R Q is selected from the group of no group, hydrogen, C2-C10 acyl, C i-Cjo alkyl and SO3H; (e) C5-C7 glycosyl;
- SRj 1 wherein R ⁇ is selected from the group ofhydrogen, Cj-Ci 0 alkyl and O3H;
- CJ-CJO alkyl optionally substituted with a substituent selected from the group of hydrogen, ORJO NHR7 > NR R9 and SRj ⁇ and
- C3-Cg cycloalkyl optionally substituted with a substituent selected from the group ofhydrogen, OR ⁇ o > NHR7, NRgR9 and SRj ⁇ providing that the compound is not /wyo-inositol.
- the present invention further provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) collecting a sample from said subject; (b) contacting said sample with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and (c) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- each of R l5 R,. s R 2 , R 2 ., R 3 , R 3 , 5 R 4s R 4 ,, R 5 , R 5 , s R 6 , and R & is independently selected from the group of;
- NHR7 wherein said R7 is selected from the group ofhydrogen; C2- C 10 acyl and C 1 -C ⁇ 0 alkyl;
- Figure 1 A shows the structure of myo-, epi- and scyllo-mositol while Figures 1 B- 1 H show the spatial reference memory version of the Morris water maze test in TgCRND8 mice.
- v ⁇ -inositol treatment did not alter cognitive function (IB).
- Figures 2A-2I show at 6 months of age, the plaque burden and astrogliosis in TgCRND ⁇ treated with epi- and scy/Zo-inositol treated mice.
- Control animals have a high plaque load and astrogliosis in the hippocampus (2A) and cerebral cortex (2B).
- Higher magnification demonstrates that astrocytic activation is not only associated with plaque load (2C).
- Epz ' -inositol treatment has a modest effect on amyloid burden with a decrease in astrogliosis (2D, 2 ⁇ and 2F).
- Scy/Zo-inositol treatment significantly decreased amyloid burden and gliosis (2G, 2H, and 21).
- FIGS 3A-3D show that the A ⁇ species, 1-42, 1-40 and 1-38, in control and treated TgCRND8 mice was indistinguishable (3A) as was the extent of APP processing (3B).
- Vascular amyloid burden was quantitated on serial sagittal sections in treated and untreated TgCRND8 mice.
- TgCRND ⁇ mice have a significant vascular amyloid burden that is associated with small and medium sized vessels, the load is decreased in scy/zO-inositol treated TgCRND8 mice (3A). Scyllo-inositol treatment significantly decreased the total vascular load in comparison to untreated and epi- inositol treated TgCRND8 mice (3C). Sc /Zo-inositol decreases plaque deposition as illustrated by the significant decrease in mean plaque size (3D).
- Figure 4 shows the effect of water on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- Figure 5 shows the effect of scyllo-mos ⁇ .6 on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- Figure 6 shows the effect of epz ' -inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- Figure 7 shows the effect of w oinositol on the cognitive function of TgCRND ⁇ and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- Figure 8 shows the effect of scy/fo-inositol, epz ' -inositol and r ⁇ y ⁇ -inositol on the cognitive function of TgCRND8 (learning phase and memory test) and compared with wild type mice using the spatial reference memory version of the Morris Water Maze in a three-day trial paradigm.
- Figure 9 shows the percentage of brain area covered with plaques in untreated TgCRND8 mice versus mice treated with scy/Zo-inositol, epz ' -inositol or myo-inositol.
- Figures 10A and 10B show the survival rates of TgCRND ⁇ mice treated with water versus epz ' -inositol or myo-inositol (10A) or versus •s , cy// ⁇ -inositol (10B).
- Figures 12A and B show the results of a spatial reference memory test in the treatment studies when performed in a 3-day trial paradigm.
- Figures 13 A and B show A ⁇ levels within the CNS after administration of various doses of scy//o-inositol were administered once daily for one month to five month old TgCRNDS mice. Soluble A ⁇ 42 levels were decreased at all doses and were significantly different from untreated controls (A). In contrast, insoluble A ⁇ 42 was not significantly different under all conditions (B). Vertical bars represent S.E.M.
- Figure 15 shows the cognitive performance of 6-month old ⁇ //o-inositol- treated TgCRND ⁇ mice compared with that of their non-transgenic littermates.
- Figures 16A-D show that at 2 months of age, the plaque burden in TgPSl x APP mice is decreased in scy/Zo-inositol treated mice.
- Control animals have a high plaque load in the hippocampus (A) and cerebral cortex (B). Scy/zo-inositol treatment significantly decreased amyloid burden (C, D). Plaque burden identified using anti- A ⁇ antibody (brown). Scale Bar 300 ⁇ m.
- Figures 17A-C show the quantification of the plaque burden in TgPSlxAPP mice after -? ⁇ y//o-inositol treatment.
- the percent brain area covered in plaques (A), mean plaque size (B) and plaque count (C) were significantly reduced.
- Vertical bars are S.E.M. DETAILED DESCRIPTION OF THE INVENTION
- the present invention discloses novel, unpredictable and unexpected properties of certain inositol stereoisomers in relation to the treatment of amyloid- related disorders such as Alzheimer's Disease. It has been surprisingly discovered that certain stereoisomers of inositol and related compounds block A ⁇ -induced progressive cognitive decline and cerebral amyloid plaque pathology, and improve survival when given to a transgenic mouse model of human Alzheimer Disease during the nascent phase of A ⁇ deposition.
- inositol stereoisomers e.g. epi- and scy// ⁇ -inositols
- the present invention describes the unexpected results that scy/Zo-inositol inhibits already established cerebral amyloid deposition, and does so in the living brain. This is not implied by the previously published in vitro data which considered only certain neuronal cell types in culture, not the complex tissues of the living brain, and only suggested that inositols might inhibit de novo aggregation, thereby having no relevance to established disease.
- the compounds of the present invention are 1,2,3,4,5,6- cyclohexanehexols, more preferably selected from the group of cis-, epi-, allo-, muco-, neo- , scyllo-, D-chiro- and L-cAzro-inositols.
- these compounds are 1,2,3,4,5-cyclohexanepentols (quercitols), more preferably selected from the group of epi-, vibo-, scyllo-, allo-, talo-, gala-, cis-, muco-, neo-, pr ⁇ t ⁇ -quercitols and enantiomers thereof.
- quercitols 1,2,3,4,5-cyclohexanepentols
- these compounds are selected from the group of a cyclohexanetetrol, a cyclohexanetriol, stereoisomer of cyclohexanetetrol, stereoisimer of cyclohexanetriol, enantiomer of cyclohexanetetrol, and enantiomer of cyclohexanetriol.
- These compounds may also be compound is pentahydxycyclohexanones or stereoisomers or enantiomers thereof. Yet again preferably, these compounds are inosose compounds selected from the group of scyZZ ⁇ -inosose, L-c/ ⁇ z ' r ⁇ -inosose-1 and L-epz ' -inosose.
- these compounds are trihydroxyxcyclohexanones, or stereoisomers or enantiomers thereof. More preferably, (-)-l- e ⁇ y-scyllo-inosose.
- these compounds are pentahydxycyclohexanones (inosose), or stereoisomers or enantiomers thereof, more preferably selected from the group of .scy/Z ⁇ -inosose, L-c/zz ' r ⁇ -inosose-l and L-epz ' -inosose.
- these compounds are trihydroxyxcyclohexanones or stereoisomers or enantiomers thereof such as (-)-l-deoxy-scyllo-mosose.
- these compounds are O-monomethyl-cyclohexanehexols or stereoisomers or enantiomers thereof, more preferably selected from the group of D- pinitol, L-quebrachitol and D-bornesitol.
- these compounds may be selected from the group of , monoaminocyclohexanepentols (inosamines), diaminocyclohexanetetrols (inosadiamines), diaminocyclohexanetriols, stereoisomers thereof, and enantiomers thereof, and pharmaceutically acceptable salts thereof such as L-ne ⁇ -inosamine, D,L- epz ' -inosamine-2, streptamine and deoxystreptamine.
- these compounds are monomercapto-cyclohexanepentols or stereoisomers or enantiomers thereof, more preferably 1L-1 - eo y-1 -mercapto-8- O-methyl-chiro-inositol.
- the most preferred compounds of the present invention are ⁇ ZZ ⁇ -inositol and scyZZo-inositol, with scyZZ ⁇ -inositol being the most preferred.
- the inositol stereoisomers of the present invention exclude zwy ⁇ -inositol and may also exclude epz ' -inositol.
- these compounds are found to be useful in treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence.
- These compounds are also found to be useful in preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions as well as causing the dissociation of abnormally aggregated proteins and/or dissolving or disrupting pre-formed or pre-deposited amyloid fibril or amyloid in a subject.
- the condition of the central or peripheral nervous system or systemic organ results in the deposition of proteins, protein fragments and peptides in beta-pleated sheats and/or fibrils and/or aggregates. More preferably, the condition of the central or peripheral nervous system or systemic organ is selected from the group of: Alzheimer's disease, presenile and senile forms; amyloid angiopathy; mild cognitive impairment; Alzheimer's disease-related dementia; tauopathy; ⁇ - synucleinopathy; Parkinson's disease; Amyotrophic Lateral Sclerosis; motor neuron Disease; Spastic paraplagia; Huntington's Disease, spinocerebellar ataxia, Freidrich's Ataxia; neurodegenerative diseases associated with intracellular and/or intraneuronal aggregates of proteins with polyglutamine, polyalanine or other repeats arising from pathological expansions of tri- or tetra-nucleotide elements within corresponding genes; cerebro vascular diseases; Down's syndrome; head trauma with post-traumatic accumulation of
- Alzheimer dementia and tauopathy selected from the group of argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism, Prion-related disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian Motor Neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tangle only dementia.
- the ⁇ -synucleinopathy is selected from the group of dementia with Lewy bodies, multiple system atrophy with glial cytoplasmie inclusions, Shy- Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, neurodegeneration with brain iron accumulation type I, olfactory dysfunction, and amyotrophic lateral sclerosis.
- the Motor Neuron Disease is associated with filaments and aggregates of neuro filament and/or superoxide dismutase proteins
- the Spastic paraplegia is associated with defective function of chaperones arid/or triple A proteins
- the spinocerebellar ataxia is DRPLA or Machado- Joseph Disease.
- the Prion related disease is selected from the group of Creutzfeldt- Jakob disease, Gerstmann-Straussler-Scheinker disease, and variant Creutzfeldt-Jakob disease and the Amyloid Polyneuropathy is Senile amyloid polyneuropathy or Systemic Amyloidosis.
- the condition of the central or peripheral nervous system or systemic organ is Parkinson's disease including familial and non-familial types. Most preferably, said condition of the central or peripheral nervous system or systemic organ is Alzheimer's disease.
- the compound is administered to the subject at a dose of about 1 mg to about 1 g per kg, preferably 1 mg to about 200 mg per kg, more preferably about 10 mg to about 100 mg per kg and most preferably about 30 mg to 70 mg per kg of the weight of said subject.
- the administration can be accomplished by a variety of ways such as orally (oral pill, oral liquid or suspension), intravenously, intramuscularly, intraperitoneally, intraderrnally, transcutaneously, subcutaneously, intranasally, sublingually, by rectal suppository or inhalation, with the oral administration being the most preferred.
- the administration of the compounds of the present invention can be undertaken at various intervals such as once a day, twice per day, once per week, once a month or continuously.
- the compounds of the present invention are administered in combination with other treatments such as beta-secretase inhibitors, gamma-secretase inhibitors (APP-specific or non-specific), epsilon-secretase inhibitors (APP-specific or non-specific), other inhibitors of beta-sheet aggregation/fibrillogenesis/ADDL formation (e.g. Alzhemed), NMDA antagonists (e.g. memantine), non-steroidal anti- inflammatory compounds (e.g. Ibuprofen, Celebrex), anti-oxidants (e.g. Vitamin E), hormones (e.g. estrogens), nutrients and food supplements (e.g.
- other treatments such as beta-secretase inhibitors, gamma-secretase inhibitors (APP-specific or non-specific), epsilon-secretase inhibitors (APP-specific or non-specific), other inhibitors of beta-sheet aggregation/fibrillogenesis/ADDL formation (e.g. Alzhemed
- Gingko biloba Gingko biloba
- acetylcholinesterase inhibitors e.g. donezepil
- muscarinic agonists e.g. AF102B (Cevimeline, EVOXAC), AF150(S), and AF267B
- anti-psychotics e.g. haloperidol, clozapine, olanzapine
- anti-depressants including tricyclics and serotonin reuptake inhibitors (e.g.
- Sertraline and Citalopram Hbr gene therapy and/or drug based approaches to upregulate neprilysin (an enzyme which degrades A ⁇ ); gene therapy and/or drug based approaches to upregulate insulin degrading enzyme (an enzyme which degrades A ⁇ ), vaccines, immunotherapeutics and antibodies to A ⁇ (e.g. ELAN AN- 1792), statins and other cholesterol lowering drugs (e.g. Lovastatin and Simvastatin), stem cell and other cell-based therapies, inhibitors of kinases (CDK5, GSK3 ⁇ , GSK3 ⁇ ) that phosphorylate TAU protein (e.g. Lithium chloride), or inhibitors of kinases that modulate A ⁇ production (GSK3 ⁇ , GSK3 ⁇ , Rho/ROCK kinases) (e.g. lithium Chloride and Ibuprofen).
- CDK5 inhibitors of kinases
- GSK3 ⁇ , GSK3 ⁇ that phosphorylate TAU protein
- the compounds of the present invention are also useful in diagnosing the presence of abnormally folded or aggregated protein and or amyloid fibril or amyloid in a subject using a method that comprises administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid.
- a sample suspected of containing abnormally folded or aggregated protein and or amyloid fibril or amyloid is collected from a subject and is contacted with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and thereafter detect the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated. protein and/or amyloid fibril or amyloid in said subject.
- said detectable signal is a fluorescent or an enzyme-linked i ⁇ rmunosorbent assay signal and said sample is whole blood (including all cellular constituents) or plasma.
- said detectable signal is a fluorescent or an enzyme-linked i ⁇ rmunosorbent assay signal and said sample is whole blood (including all cellular constituents) or plasma.
- the compounds of the present invention can abrogate the cerebral accumulation of A ⁇ , the deposition of cerebral amyloid plaques, and cognitive decline in a transgenic mouse model of Alzheimer Disease when given during the "late presymptomatic" phase, prior to the onset of overt cognitive deficits and amyloid neuropathology in these mice. Furthermore, even when these compounds are given after the onset of cognitive deficits and amyloid plaque neuropathology, they can effectively reverse the amyloid deposition and neuropathology. Importantly, the mechanism of action of these compounds follows a rational design based upon their capacity to modulate the assembly of A ⁇ monomers into neurotoxic oligomers and/or protofibrils.
- TgCRND8 mice are a robust murine model of Alzheimer's disease as described by Janus et al. (Nature 408:979-982 (2000). They express a human amyloid precursor protein (APP695) transgene under the regulation of the Syrian hamster prion promoter on a C3H/B6 outbred background. The human APP695 transgene bears two mutations that cause AD in humans (K670N/M671L and V717F).
- APP695 human amyloid precursor protein
- TgCRND ⁇ mice have progressive spatial learning deficits that are accompanied by rising cerebral A ⁇ levels and by increasing number of cerebral extracellular amyloid plaques that are similar to those seen in the brains of humans with AD (C. Janus et al., Nature 408:979-982 (2000)).
- mice and non-transgenic littermates were either untreated, or were given a compound of the present invention as indicated below at 30mg/day/mouse beginning at age of about 6 weeks. The mice were followed for outcome measures cognitive function, brain A ⁇ levels, brain pathology, and survival at 4 months and 6 months of age.
- mice Experimental groups of TgCRND ⁇ mice were fed myo-, epi- and sc ZZo-inositol at 30 mg/mouse/day. Two cohorts entered the study at 6 weeks of age and outcomes were analyzed at 4- and 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines. Behavioral tests - After non-spatial pre-training, mice underwent place discrimination training for 5 days with 4 trials per day. Behavioral data was analyzed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- ANOVA factorial analysis of variance
- Amyloid plaque burden was assessed using Leco JA-3001 image analysis software interfaced with Leica microscope and Hitachi KP-M1U CCD video camera. Vascular burden was analyzed similarly and a dissector was used to measure the diameter of affected vessels.
- Plasma and Cerebral A ⁇ Content - Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/lOOmM NaCI for soluble A ⁇ levels or cold formic acid for the isolation of total A ⁇ . After neutralization the samples were diluted and analyzed for A ⁇ 40 and A ⁇ 42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean ⁇ SEM reported. Western blot analyses were performed on all fractions using urea gels for A ⁇ species analyses. A ⁇ was detected using 6E10 (BIOSOURCE International) and Enhanced Chemiluminenscence (Amersham).
- Sections were irnrnunolabelled for astrocytes with anti-rat GFAP IgG 2a (Dako; diluted 1 :50) and for microglia with anti-rat CD68 IgG2b (Dako; 1 :50).
- Digital images were captured using a Coolsnap digital camera (Photometries, Tuscon, Arizona) mounted to a Zeiss Axioscope 2 Plus microscope. Images were analysed using Openlab 3.08 imaging software (Improvision, Lexington MA).
- Example 2 Prevention of cognitive deficits
- the cognitive function of TgCRND ⁇ mice was assessed using the spatial reference memory version of the Morris Water Maze using a five-day trial paradigm ( Figures 1C-1H).
- ANOVA analysis of variance
- TgCRND ⁇ mice treated with either epi- or _? ⁇ y// ⁇ -inositol performed significantly better than untreated TgCRND ⁇ mice (p ⁇ 0.02; Figs. 1C and D).
- epz ' -inositol treated TgCRND ⁇ mice had a slightly slower learning curve during the first three days of training.
- epz ' -inositol treated TgCRNDS mice were not statistically different from their non-Tg littermates (Fig. 2E).
- scyllo- inositol treated TgCRND ⁇ mice were indistinguishable from non-Tg littermates on all days.
- TgCRND ⁇ mice have high plasma A ⁇ concentrations at 4-months of age and remain constant at 6 months of age even though CNS plaque load is still rising at 6-months of age (Table 1). Neither epz ' -inositol nor sey/Zo-inositol treatment had any effect on plasma A ⁇ levels in comparison to untreated TgCRNDS mice (p-0.89).
- Astroglial and microglial reactions are neuropathological features both of human AD and of all amyloid mouse models (Irizarry et al., J Neuropathol Exp Neurol 56 , 965, 1997; K. D. Bornemann et al. Ann N Y Acad Sci. 90 ⁇ , 260, 2000). Therefore, the effect of epi- and scy/Z ⁇ -inositol treatment was investigated on astrogliosis and microgliosis in the brains of TgCRND8 mice ( Figures 3A-3D). Serial sagittal sections were stained with the astrocytic marker glial fibrillary acidic protein (GFAP) and quantitated for percent brain area covered by astrogliosis.
- GFAP astrocytic marker glial fibrillary acidic protein
- TgCRND ⁇ mice have a high basal astrogliosis at 4-months of age (0.459 ⁇ 0.04 ⁇ %), which increases slightly by 6-months of age (0.5 ⁇ 4 ⁇ 0.0 ⁇ 9%), and which is not restricted to plaque areas ( Figures 2A-C).
- Microglial activation was also significantly attenuated in scy// ⁇ -inositol treated TgCRND ⁇ mice (0.20 ⁇ 0.008% brain area) when compared to age- and sex-matched untreated TgCRNDS mice (0.31 ⁇ 0.01%; p ⁇ .001).
- Alzheimer's disease is characterized by the presence of both parenchymal and vascular amyloid deposits.
- TgCRND ⁇ mice approximately 0.03% of the brain area is associated with vascular amyloid.
- No difference could be detected in the vascular amyloid burden after epz ' -inositol treatment at 6 months of age ( Figure 3C).
- Treatment with ⁇ -inositol did not affect overall survival significantly ( Figure 10A).
- treatment of wild type mice with sc ZZo-inositol had no effect either on survival or on other parameters such as weight, fur condition or cage behavior.
- Example 7 Treatment and Reversal of amyloid deposition
- scyllo-inositol inhibits both parenchymal and cerebrovascular amyloid deposition and results in improved survival and cognitive function in the TgCRND8 mouse model of Alzheimer disease.
- most Alzheimer's disease patients will likely seek treatment only once symptomatic, and when A ⁇ oligomerization, deposition, toxicity and plaque formation are already well advanced within the CNS.
- a pilot study was therefore initiated on 5 month old TgCRND ⁇ mice. These mice have significant A ⁇ and plaque burdens that are comparable to those in the brain of humans with AD.
- mice mice were fed myo-, epi- and scyllo- inositol at 30 mg/mouse/day. A cohort entered the study at 5 months of age and outcomes were analyzed at 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines.
- Behavioral Test - Reversal Study Mice entered the Morris water maze test with a hidden platform on day one without pretraining. Mice were tested for 3 days with six trials per day. On the fourth day, the platform was removed from the pool and each mouse received one 30-s swim probe trial. On the last day the animals underwent a cue test in order to evaluate swimming ability, eye sight and general cognition. The cue test is composed at the platform being placed in a different quadrant than that used for testing and is tagged with a flag. Animals are allowed 60 s to find the platform. Animals that do not find the platform are not used in the final analyses of spatial memory. Behavioural data was analysed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- ANOVA factorial analysis of variance
- Plasma and Cerebral A ⁇ Content - Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/lOOmM NaCI for soluble A ⁇ levels or cold formic acid for the isolation of total A ⁇ . After neutralization the samples were diluted and analyzed for A ⁇ 40 and A ⁇ 42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean ⁇ SEM reported.
- ANOVA analysis of variance
- TgCRND8 mice were significantly impaired in comparison to wild type littermates (Figure 4).
- Example 10 Efficacy of ⁇ /fo-inositol for the treatment of disease bearing TgCRND8 mice.
- TgCRND ⁇ mice were either treated for 2 days with allo- inositol, or were untreated.
- the dosage and oral administration of compounds, and the behavioral and neurochemical assays were the same as those employed in the above treatment experiments.
- Cerebral A ⁇ levels were analyzed for treatment versus untreated TgCRND ⁇ mice to determine whether improved behavior could be correlated with changes in A ⁇ (Table 4).
- ⁇ ZZo-inositol treatment reduced soluble A ⁇ 42 (20% reduction, p ⁇ 0.05) an effect similar to that seen for scyllo- inositol.
- y ⁇ ZZ ⁇ -inositol did not significantly alter insoluble A ⁇ 42 or A ⁇ 40 (soluble and insoluble pools).
- One possible explanation for the decrease in A ⁇ 42 is clearance of A ⁇ 42 in the periphery with a subsequent increase in plasma A ⁇ 42.
- Tg PSl x APP mice are an enhanced model of Alzheimer's disease which express a mutant human PSl transgene encoding two familial mutations (M146L and L2 ⁇ 6V) in conjunction with the human APP transgene encoding the Indiana and Swedish familial mutations. These animals develop robust expression of cerebral A ⁇ levels and amyloid deposition by 30-45 days of age. In a prophylactic trial, TgPSlxAPP mice were treated with -fcy/Z ⁇ -inositol from weaning and were assessed for effects on neuropathology at 2 months of age ( Figures 16 and 17).
- scyllo- inositol treated TgPSlxAPP mice displayed a significant decrease in all measures of plaque burden at 2 months of age.
- TgCRND ⁇ mice were treated with a simple sugar of similar molecular weight, mannitol. At 6 months of age, mannitol treated TgCRND ⁇ mice were indistinguishable from untreated TgCRND ⁇ mice (Fig. 11 A) and were significantly different from mannitol treated non-Tg littermates (Fig. 1 IB). Mannitol had no effect on the behaviour of non-Tg mice, since mannitol treated non-Tg mice were indistinguishable from untreated non-Tg mice.
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